Sennoside a From  <i>Rheum Palmatum</i> L. Is a Novel Inhibitor Targeting Caspase-1

The assembling of inflammasomes drive caspase-1 activation which further undertakes the proinflammatory cytokines secretion and downstream pyroptosis. Discovery of novel caspase-1 inhibitors is pivotal to develop new therapeutic means for inflammasome-involved diseases. In our present study, sennoside A (Sen A) potently inhibit the enzymatic activity of caspase-1 in vitro. Sen A considerably decreased IL-1β production in macrophages stimulated by LPS plus ATP, nigericin or MSU, as well as poly (dA:dT) transfection, and rescued ROS-involved pyroptosis via caspase-1 inhibition. Mechanistically, Sen A not only suppresses the assembly of both NLRP3 and AIM2 inflammasome, but also affected the priming process of NLRP3 inflammasome by blocking NF-κB signaling. Sen A significantly ameliorated pathophysiological effect in LPS-, MSU- and carrageenan-challenged rodent models through suppressing inflammasome activation. Furthermore, P2X7 was indispensable for Sen A inhibiting NLRP3 inflammasome since it failed to further decrease IL-1β and IL-18 production in LPS+ATP-stimulated BMDMs which transfected with P2X7 siRNA. Sen A also restrained the large pore-forming functionalities of the P2X7R as verified by YO-PRO-1 uptake assay. Taken together, Sen A inactivates caspase-1 to inhibit the NLRP3 and AIM2 inflammasome-involved inflammation in a P2X7-dependent manner, making it an attractive candidate of caspase-1 small-molecular inhibitor.